Background:Receptor-interacting protein kinases(RIPKs)regulate cell death,inflammation,and immune responses,yet their roles in cancer are not fully understood.This study investigates the expression,genomic alterations...Background:Receptor-interacting protein kinases(RIPKs)regulate cell death,inflammation,and immune responses,yet their roles in cancer are not fully understood.This study investigates the expression,genomic alterations,and functional implications of RIPK family members across various cancers.Methods:We collected multi-omics data from The Cancer Genome Atlas and other public databases,including gene expression,copy number variation(CNV),mutation,methylation,tumor mutation burden(TMB),and microsatellite instability(MSI).Differential expression and survival analyses were performed using DESeq2 and Cox proportional hazards models.CNV and mutation data were analyzed with GISTIC2 and Mutect2,and methylation data with the ChAMP package.Correlations with TMB and MSI were assessed using Pearson coefficients,and gene set enrichment analysis was conducted with the MSigDB Hallmark gene sets.Results:RIPK family members show significant differential expression in various cancers,with RIPK1 and RIPK4 frequently altered.Survival analysis reveals heterogeneous impacts on overall survival.CNV and mutation analyses identify high alteration frequencies for RIPK2 and RIPK7,affecting gene expression.RIPK1 and RIPK7 are hypermethylated in several cancers,inversely correlating with RIPK3 expression.RIPK1,RIPK2,RIPK5,RIPK6,and RIPK7 correlate positively with TMB,while RIPK3 shows negative correlations in some cancers.MSI analysis indicates associations with DNA mismatch repair.G ene set enrichment analysis highlights immune-related pathway enrichment for RIPK1,RIPK2,RIPK3,and RIPK6,and cell proliferation and DNA repair pathways for RIPK4 and RIPK5.RIPK family members showed heterogeneous alterations across cancers:for example,RIPK7 was mutated in up to~15%of u terine c orpus e ndometrial c arcinoma and l ung s quamous c ell c arcinoma cases,and RIPK1 and RIPK7 exhibited frequent promoter hypermethylation in multiple tumor types.Several genes displayed context-dependent associations with overall survival and with TMB/MSI.Conclusion:This pan-cancer analysis of the RIPK family reveals their diverse roles and potential as biomarkers and therapeutic targets.The findings emphasize the importance of RIPK genes in tumorigenesis and suggest context-dependent functions across cancer types.Further studies are needed to explore their mechanisms in cancer development and clinical applications.展开更多
Background:Heat shock protein B8(HSPB8)is implicated in autophagy,and its aberrant expression has been linked to both the ini-tiation and progression of tumors.However,the role and function of HSPB8 in colorectal canc...Background:Heat shock protein B8(HSPB8)is implicated in autophagy,and its aberrant expression has been linked to both the ini-tiation and progression of tumors.However,the role and function of HSPB8 in colorectal cancer(CRC)and across multiple cancer types remain unclear.This study aimed to map the transcriptome of autophagy-related genes in CRC and to conduct a pan-cancer analysis of HSPB8 as both a prognostic and immunological biomarker.Methods:We performed bioinformatics analyses on GSE113513 and GSE74602 to identify differentially expressed genes(DEGs)in CRC.These DEGs were then compared with autophagy-related genes to identify critical overlapping genes.The Kaplan-Meier plotter was used to verify the ex-pression of autophagy-linked DEGs and evaluate its prognostic value.The protein expression of Hub gene in CRC was analyzed using the Human Protein Atlas database.The cBioPortal was used to analyze the type and frequency of Hub gene mutations.The TIMER(Tumor Immune Estimation Resource)database was used to study the correlation between HSPB8 and immune infiltration in CRC.Results:In total,825 DEGs were identified,including 8 autophagy-linked DEGs:ATIC,MYC,HSPB8,TNFSF10,BCL2,TP53INP2,ITPR1,and NKX2-3.Survival analysis showed that increased HSPB8 expression significantly correlates with poor prognosis in patients with CRC(p<0.05).HSPB8 was also found to be differentially expressed in various cancer types,correlating with both prognosis and immune infiltration.Further,changes in HSPB8 methylation and phosphorylation status were observed across several cancers,suggesting potential regulatory mechanisms.Therefore,HSPB8 may serve as a crucial prognostic and immunological biomarker in CRC and other cancers.Conclusions:This study provides new insights into the role of autophagy-related genes in cancer progression and highlights HSPB8 as a potential target for cancer diagnostics and therapy.展开更多
Background:Aberrant expression of RNA-binding proteins(RBPs)has been linked to a variety of diseases,including hematological disorders,cardiovascular diseases,and multiple types of cancer.Heterogeneous nuclear ribonuc...Background:Aberrant expression of RNA-binding proteins(RBPs)has been linked to a variety of diseases,including hematological disorders,cardiovascular diseases,and multiple types of cancer.Heterogeneous nuclear ribonucleoprotein C(HNRNPC),a member belonging to the heterogeneous nuclear ribonucleoprotein(hnRNP)family,plays a pivotal role in nucleic acid metabolism.Previous studies have underscored the significance of HNRNPC in tumorigenesis;however,its specific role in malignant tumor progression remains inadequately characterized.Methods:We leveraged publicly available databases,including The Cancer Genome Atlas(TCGA),to explore the potential involvement of HNRNPC across various cancers.Additionally,we performed experimental validation studies focused on liver cancer.Results:Our analysis revealed that HNRNPC is overexpressed in a wide range of common malignancies,including liver and lung cancers,and is strongly linked to unfavorable outcomes.Furthermore,HNRNPC was observed to be closely linked to tumor immunity.Through immune checkpoint analysis and immune cell infiltration assessment,HNRNPC emerged as a potential target for modulating tumor immunotherapy.Notably,silencing of HNRNPC markedly inhibited the proliferation,metastasis,and infiltration of liver cancer cells.Conclusion:In summary,our findings highlight HNRNPC as a prognostic marker in various cancers,including liver cancer,and suggest its involvement in shaping the tumor immune microenvironment.These insights offer potential avenues for improving clinical outcomes in tumors with elevated HNRNPC expression,particularly through immunotherapeutic strategies.展开更多
Background:NDC80 is pivotal in cell division,particularly in regulating the G2/M transition and mitotic progression.Recent studies have demonstrated that NDC80 is significantly overexpressed in multiple solid tumors.F...Background:NDC80 is pivotal in cell division,particularly in regulating the G2/M transition and mitotic progression.Recent studies have demonstrated that NDC80 is significantly overexpressed in multiple solid tumors.Further analysis has suggested that its high expression is significantly associated with an elevated pathological grade,increased metastatic risk,and shortened overall survival in patients with cancer.However,its precise role in pan-cancer development,progression,and prognosis remains unclear.Methods:We conducted a multi-omics analysis of NDC80 using genomic,transcriptomic,and proteomic data from 33 cancer types in The Cancer Genome Atlas,Clinical Proteomic Tumor Analysis Consortium,Genotype-Tissue Expression,and Human Protein Atlas.Results:The results demonstrated frequent NDC80 mutations across multiple malignancies and significantly elevated expression in tumor tissues compared with that in their normal counterparts,correlating with worse overall and disease-free survival.Moreover,NDC80 expression was strongly associated with oncogenic pathways,key protein regulators,cellular components,myeloid-derived suppressor cell infiltration,ESTIMATE scores,and cancer-related signaling networks.Conclusions:These findings underscore the potential of NDC80 as a prognostic biomarker and therapeutic target for cancer treatment.展开更多
BACKGROUND Ectonucleoside triphosphate diphosphohydrolase 6(ENTPD6),a member of the ENTPD family,has been implicated in certain cancers,yet a comprehensive analysis across multiple cancer types remains lacking.AIM To ...BACKGROUND Ectonucleoside triphosphate diphosphohydrolase 6(ENTPD6),a member of the ENTPD family,has been implicated in certain cancers,yet a comprehensive analysis across multiple cancer types remains lacking.AIM To systematically evaluate ENTPD6’s expression,prognostic significance,and functions across multiple cancer types.METHODS In this study,we performed a pan-cancer analysis to investigate the correlation between ENTPD6 expression and various factors,including prognosis,genetic alterations,epigenetic modification,immune infiltration,immunotherapy responses,functional enrichment,and drug sensitivity.A tissue microarray of gastrointestinal tumors was used to validate differential ENTPD6 protein expression.RESULTS Pan-cancer analysis revealed that ENTPD6 expression was significantly elevated in many cancers.Immunohistochemistry staining analysis revealed that ENTPD6 expression was significantly higher in esophageal carcinoma,stomach adenocarcinoma,colon adenocarcinoma,rectal adenocarcinoma,and pancreatic adenocarcinoma compared to normal tissues.Furthermore,ENTPD6 expression was strongly associated with immune-infiltrating cells,particularly clusters of differentiation 8+T cells and natural killer cells,and correlated with immune-related genomic features including tumor mutational burden and microsatellite instability.Pathway analysis indicated that ENTPD6 expression was primarily linked to purine and pyrimidine metabolism pathways.Drug sensitivity analysis revealed that high ENTPD6 expression was sensitive to RDEA119,selumetinib,and PD-0325901.CONCLUSION This pan-cancer study elucidates the pivotal role of ENTPD6 in tumor progression and establishes its potential as a therapeutic target for immunotherapeutic approaches in specific malignancies.展开更多
Background:Rho GDP dissociation inhibitor 2(ARHGDIB),a key regulator of Rho GTPase,plays a significant role in the onset and progression of cancer by participating in various biological processes.However,the diverse b...Background:Rho GDP dissociation inhibitor 2(ARHGDIB),a key regulator of Rho GTPase,plays a significant role in the onset and progression of cancer by participating in various biological processes.However,the diverse biological roles of ARHGDIB across pan-cancer remain systematically and comprehensively unexplored.We aimed to elucidate the diagnostic and prognostic roles of ARHGDIB and its potential tumor-related mechanisms in human cancers,using bioinformatics approaches.Methods:Data on 33 tumor types were downloaded from The Cancer Genome Atlas,and R software was used to statistically analyze ARHGDIB expression levels and prognostic significance across pan-cancer.Western blot was used to verify the protein expression of ARHGDIB in breast cancer and liver cancer cell lines.Additionally,various databases,including UALCAN,GEPIA,cBioPortal,TIMER,CancerSEA,GSCALite,and GSEA,were used to examine ARHGDIB protein expression across pan-cancer,its correlation with tumor pathological staging,ARHGDIB mutation types and frequencies,and immune cell infiltration.Furthermore,functional analyses at the single-cell level,drug sensitivity assessments,and explorations of related signaling pathways were performed.Results:ARHGDIB exhibits abnormal expression at mRNA and protein levels across various cancers.Western blot results show that ARHGDIB is highly expressed in breast cancer and liver cancer cells.ARHGDIB influences the prognosis of lower-grade glioma,bladder cancer,sarcoma,and skin cutaneous melanoma.It exhibits the highest frequency of gene alterations in uterine carcinosarcoma,primarily characterized by gene amplification.Additionally,ARHGDIB is strongly associated with immune-infiltrating cells and immune checkpoints in the tumor microenvironment.It potentially influences cancer progression through multiple signaling pathways.Conclusions:ARHGDIB is a potential prognostic marker in various cancers and a crucial regulator of the tumor microenvironment.It represents a promising therapeutic target by modulating cancer progression through multiple biological behaviors and signaling pathways.展开更多
BACKGROUND Although transmembrane protein 106C(TMEM106C)has been elucidated to be overexpressed in cancers,its underlying mechanisms have not yet been fully understood.AIM To investigate the expression levels and mole...BACKGROUND Although transmembrane protein 106C(TMEM106C)has been elucidated to be overexpressed in cancers,its underlying mechanisms have not yet been fully understood.AIM To investigate the expression levels and molecular mechanisms of TMEM106C across 34 different cancer types,including liver hepatocellular carcinoma(LIHC).METHODS We analyzed TMEM106C expression patterns in pan-cancers using microenvironment cell populations counter to evaluate its association with the tumor microenvironment.Gene set enrichment analysis was conducted to identify molecular pathways related to TMEM106C.Chromatin immunoprecipitation followed by sequencing(ChIP-seq)analysis was conducted to identify upstream transcriptional regulators of TMEM106C.In LIHC,we examined mRNA profiles,performed in-house quantitative polymerase chain reaction,immunohistochemistry,and constructed a co-expression gene network.Functional assays,including cell counting kit-8,cell cycle,apoptosis,migration,and invasion,were conducted.The effect of nitidine chloride(NC)on LIHC xenograft was evaluated through RNA sequencing and molecular docking.Finally,potential therapeutic agents targeting TMEM106C were predicted.RESULTS TMEM106C was significantly overexpressed in 27 different cancer types and presaged poor prognosis in four of these types,including LIHC.Across pan-cancers,TMEM106C was inversely correlated to the abundances of immune and stromal cells.Furthermore,TMEM106C was significantly linked to cell cycle and DNA replication pathways in pan-cancers.ChIP-seq analysis predicted CCCTC-binding factor as a pivotal transcriptional factor targeting the TMEM106C gene in pan-cancers.Integrated analysis showed that TMEM106C was upregulated in 4657 LIHC compared with 3652 normal liver tissue[combined standardized mean difference=1.31(1.09,1.52)].Inhouse LIHC samples verified the expression status of TMEM106C.Higher TMEM106C expression signified worse survival conditions in LIHC patients treated with sorafenib,a tyrosine kinase inhibitor(TKI).Co-expressed analysis revealed that TMEM106C were significantly enriched in the cell cycle pathway.Knockout experiments demonstrated that TMEM106C plays a crucial role in LIHC cell proliferation,migration,and invasion,with cell cycle arrest occurring at the DNA synthesis phase,and increased apoptosis.Notably,TMEM106C upregulation was attenuated by NC treatment.Finally,TMEM106C expression levels were significantly correlated with the drug sensitivity of anti-hepatocellular carcinoma agents,including JNJ-42756493,a TKI agent.CONCLUSION Overexpressed TMEM106C was predicted as an oncogene in pan-cancers,which may serve as a promising therapeutic target for various cancers,including LIHC.Targeting TMEM106C could potentially offer a novel direction in overcoming TKI resistance specifically in LIHC.Future research directions include in-depth experimental validation and exploration of TMEM106C’s role in other cancer types.展开更多
BACKGROUND Although chronic-phase chronic myeloid leukemia(CP-CML)is treatable and nearly curable in about 50%of patients,accelerated-phase chronic myeloid leukemia(AP-CML)shows concerning drug resistance,while blast ...BACKGROUND Although chronic-phase chronic myeloid leukemia(CP-CML)is treatable and nearly curable in about 50%of patients,accelerated-phase chronic myeloid leukemia(AP-CML)shows concerning drug resistance,while blast crisis chronic myeloid leukemia(BC-CML)is highly lethal.Advances in whole exome sequencing(WES)reveal pan-cancer mutations in BC-CML,supporting mutation-guided therapies beyond Breakpoint cluster region-Abelson.Artificial intelligence(AI)and machine learning(ML)enable genomic stratification and drug repurposing,addressing overlooked actionable mutations.AIM To stratify BC-CML into molecular subtypes using WES,ML,and AI for precision drug repurposing.METHODS Included 123 CML patients(111 CP-CML,5 AP-CML,7 BC-CML).WES identified pan-cancer mutations.Variants annotated via Ensembl Variant Effect Predictor and Catalogue of Somatic Mutations in Cancer(COSMIC).ML(principal component analysis,K-means)stratified BC-CML.COSMIC signatures and PanDrugs prioritized drugs.Analysis of variance/Kruskal-Wallis validated differences(P<0.05).RESULTS In this exploratory,hypothesis-generating study of BC-CML patients(n=7),we detected over 2500 somatic mutations.ML identified three BC-CML clusters:(1)Cluster 1[breast cancer susceptibility gene 2(BRCA2),TP53];(2)Cluster 2[isocitrate dehydrogenase(IDH)1/2,ten-eleven translocation 2];and(3)Cluster 3[Janus kinase(JAK)2,colony-stimulating factor 3 receptor],with distinct COSMIC signatures.Therapies:(1)Polyadenosinediphosphate-ribose polymerase inhibitors(olaparib);(2)IDH inhibitors(ivosidenib);and(3)JAK inhibitors(ruxolitinib).Mutational burden,signatures,and targets varied significantly across clusters,supporting precision stratification.CONCLUSION This WES-AI-ML framework provides mutation-guided therapies for BC-CML,enabling real-time stratification and Food and Drug Administration-approved drug repurposing.While this exploratory study is limited by its small sample size(n=7),it establishes a methodological framework for precision oncology stratification that warrants validation in larger,multi-center cohorts.展开更多
B and T-lymphocyte attenuator(BTLA)plays an immunosuppressive role by inhibiting T-and B-cell functions.BTLA is associated with a variety of diseases,especially cancer immunity.However,the function of BTLA in various ...B and T-lymphocyte attenuator(BTLA)plays an immunosuppressive role by inhibiting T-and B-cell functions.BTLA is associated with a variety of diseases,especially cancer immunity.However,the function of BTLA in various cancers and its clinical prognostic value have still not been comprehensively analyzed.This study aimed to identify the relationship between BTLA and cancer from the perspectives of differences in BTLA expression,its clinical value,immune infiltration,and the correlation with immune-related genes in various cancers.Data regarding mRNA expression,miRNA expression,lncRNA expression,and clinical data of patients of 33 existing cancers were collected from the TCGA database.Target miRNA of BTLA and the lncRNA that interacts with the target miRNA were obtained from the StarBase database.Based on bioinformatics analysis methods,the relationship between various types of cancers and BTLA was thoroughly investigated,and a competing endogenous RNA network of BTLA,target miRNA,and interacting lncRNA was constructed.The Kaplan-Meier(KM)prognostic analysis of BTLA and target miRNA(has-miR-137)in various types of cancers was completed using the KM plotter.BTLA expression varied in different cancers,with statistical significance in nine cancer types.KM plotter to analyze the overall survival(OS)and regression-free survival prognosis of cancer patients revealed that the BTLA expression was statistically different in the OS of 11 types of cancers out of 21 types of cancers;the OS of 8 type of cancers was also statistically different.Correlation analysis of tumor immune genes revealed a positive correlation of BTLA expression with immunosuppressive gene(CTLA4 and PDCD1)expression.Gene Set Enrichment Analysis showed that BTLA and its co-expressed genes mainly act through biological processes and pathways,including immune response regulation,cell surface receptor signaling pathway,antigen binding,antigen receptor-mediated signaling pathway,and leukocyte migration.BTLA has the potential as a prognostic marker for CLL,COAD,NSCLC,and OV and a diagnostic marker for CLL,COAD,and KIRC.BTLA has a close and complex relationship with the occurrence and development of tumors,and cancer immunotherapy for BTLA is worthy of further analysis.展开更多
Apolipoprotein E(APOE),a gene identified as one of the strongest genetic factors contributing to the risk determinant of developing late-onset Alzheimer’s disease(AD),may also contribute to the risk of cancer.However,...Apolipoprotein E(APOE),a gene identified as one of the strongest genetic factors contributing to the risk determinant of developing late-onset Alzheimer’s disease(AD),may also contribute to the risk of cancer.However,no pan-cancer analysis has been conducted specifically for the APOE gene.In this study,we investigated the oncogenic role of the APOE gene across cancers by GEO(Gene Expression Omnibus)and TCGA(The Cancer Genome Atlas).Based on the available data,we found that most cancer types overexpress APOE,and clear associations exist between the expression level of APOE and prognosis in tumor patients.The expression of APOE also correlates with certain gender-associated tumors including,ovarian cancer,uterine carcinosarcoma,and breast cancer.However,there is a significant negative association between cancer-associatedfibroblast infiltration levels and the expression level of APOE in testicular germ cell tumors.Moreover,acute inflammatory response and protein-activation cascade-associated functions play an important role in the functional mechanisms of APOE.The present pan-cancer analysis of APOE shows that the protein phosphorylation,DNA methylation,and genetic alterations of APOE have a significant clinical relevance for survival prognosis and immune cell infiltration.This novel pan-cancer study outlines the current understanding of APOE oncogenic roles across thirty-three cancers and highlights the complex association between AD and cancers.展开更多
Objective:Ankyrin repeat domain-containing protein 6(ANKRD6)is an ankyrin repeat-containing protein which is structurally related to vertebrate inversin and Drosophila Diego.However,the correlations between ANKRD6 and...Objective:Ankyrin repeat domain-containing protein 6(ANKRD6)is an ankyrin repeat-containing protein which is structurally related to vertebrate inversin and Drosophila Diego.However,the correlations between ANKRD6 and tumor-infiltrating immune cells in cancers is not clear.Methods:ANKRD6 expression was analyzed by Oncomine,Tumor Immune Estimation Resource(TIMER)and Gene Expression Profiling Interactive Analysis(GEPIA).PrognoScan and GEPIA were used to evaluate the influence of ANKRD6 on clinical prognosis.TIMER and CIBERSORT were used to analyze correlations between ANKRD6 expression levels and tumor immune cell infiltrates.Immunohistochemical analysis of the relationship between ANKRD6 expression and overall survival,as well as the relationship between ANKRD6 expression and M2 macrophage infiltration,was performed.Results:High level of ANKRD6 expression was associated with poor prognosis of colon cancer.ANKRD6 expression level was positively correlated with infiltrating levels of CD8+T cells,CD4+T cells,macrophages,neutrophils and dendritic cells in colon cancer by using TIMER.Using CIBERSORT,we found that in plasma cells,CD8+T cells,CD4+memory resting T cells,follicular helper T cells and activated natural killer cells were significantly lower in the ANKRD6-high group than in the ANKRD6-low group.M0 and M2 macrophages were significantly higher in the ANKRD6-high group than in the ANKRD6-low group.Immunohistochemistry confirmed that M2 macrophage infiltration in the ANKRD6-high group significantly increased.Conclusions:The high ANKRD6 expression is associated with poor prognosis of colon cancer.ANKRD6 expression is positively correlated with M2 macrophage infiltration in colon cancer.展开更多
Sterol o-acyltransferase1(SOAT1)is an enzyme that regulates lipid metabolism.Nevertheless,the predictive value of SOAT1 regarding immune responses in cancer is not fully understood.Herein,we aimed to expound the predi...Sterol o-acyltransferase1(SOAT1)is an enzyme that regulates lipid metabolism.Nevertheless,the predictive value of SOAT1 regarding immune responses in cancer is not fully understood.Herein,we aimed to expound the predictive value and the potential biological functions of SOAT1 in pan-cancer.Raw data related to SOAT1 expression in 33 different types of cancer were acquired from The Cancer Genome Atlas(TCGA)and Genotype-Tissue Expression(GTEx)databases.SOAT1 expression was significantly increased in most cancers and showed a distinct correlation with prognosis.This enhanced expression of the SOAT1 gene was confirmed by evaluating SOAT1 protein expression using tissue microarrays.In addition,we found significant positive associations between SOAT1 expression levels and infiltrating immune cells,including T cells,neutrophils,and macrophages.Moreover,the co-expression analysis between SOAT1 and immune genes showed that many immune-related genes were increased with enhanced SOAT1 expression.A gene set enrichment analysis(GSEA)revealed that the expression of SOAT1 correlated with the tumor microenvironment,adaptive immune response,interferon signaling,and cytokine signaling.These findings indicate that SOAT1 is a potential candidate marker for predicting prognosis and a promising target for tumor immunotherapy in cancers.展开更多
Background:Both eczema and tumor are associated with immune disorders.Although several investigations have observed the rela-tionship between eczema and certain cancers,evidence for causality is lacking.Methods:We con...Background:Both eczema and tumor are associated with immune disorders.Although several investigations have observed the rela-tionship between eczema and certain cancers,evidence for causality is lacking.Methods:We conducted a two-sample Mendelian randomization(MR)study to examine and explore the genetic association between eczema and pan-cancers.Upon satisfying the three core assumptions of MR,we analyzed the causality between eczema and 15 site-specific cancers utilizing an inverse variance weighted method.We verified the results through a series of sensitivity and reverse direction analyses.The exposure and outcome datasets were substituted from the FinnGen and genome-wide association studies catalog data-bases.A meta-analysis on primary and validation analyses was performed to combine the estimates of MR study.Results:Based on the MR analysis results,eczema was associated with an increased risk of lung cancer(odds ratio[OR]=1.0427,95%confidence interval[CI]=1.0082–1.0783,P=0.0148)and brain cancer(OR=1.0285,95%CI=1.0120–1.0452,P=0.0007)and de-creased risk of colorectal cancer(OR=0.9324,95%CI=0.8774–0.9909,P=0.0242)and malignant neoplasm of the kidney(OR=0.9323,95%CI=0.8834–0.9839,P=0.0108).The sensitivity analysis indicated that the results were stable and reliable,and the reverse MR analyses demonstrated no causation between the cancers of interest and eczema.Conclusions:Our results identified eczema as a genetic risk factor for lung and brain cancer and a protective factor for colorectal cancer and malignant neoplasm of the kidney.No connection was observed between eczema and other cancers.Further evidence from epide-miological and mechanistic studies is needed to elucidate these findings in detail.展开更多
Objective: DNA damage response(DDR) deficiency has emerged as a prominent determinant of tumor immunogenicity. This study aimed to construct a DDR-related immune activation(DRIA) signature and evaluate the predictive ...Objective: DNA damage response(DDR) deficiency has emerged as a prominent determinant of tumor immunogenicity. This study aimed to construct a DDR-related immune activation(DRIA) signature and evaluate the predictive accuracy of the DRIA signature for response to immune checkpoint inhibitor(ICI) therapy in gastrointestinal(GI) cancer.Methods: A DRIA signature was established based on two previously reported DNA damage immune response assays. Clinical and gene expression data from two published GI cancer cohorts were used to assess and validate the association between the DRIA score and response to ICI therapy. The predictive accuracy of the DRIA score was validated based on one ICI-treated melanoma and three pan-cancer published cohorts.Results: The DRIA signature includes three genes(CXCL10, IDO1, and IFI44L). In the discovery cancer cohort, DRIA-high patients with gastric cancer achieved a higher response rate to ICI therapy than DRIA-low patients(81.8% vs. 8.8%;P < 0.001), and the predictive accuracy of the DRIA score [area under the receiver operating characteristic curve(AUC) = 0.845] was superior to the predictive accuracy of PD-L1 expression, tumor mutational burden, microsatellite instability, and Epstein–Barr virus status. The validation cohort demonstrated that the DRIA score identified responders with microsatellite-stable colorectal and pancreatic adenocarcinoma who received dual PD-1 and CTLA-4 blockade with radiation therapy. Furthermore, the predictive performance of the DRIA score was shown to be robust through an extended validation in melanoma, urothelial cancer, and pan-cancer.Conclusions: The DRIA signature has superior and robust predictive accuracy for the efficacy of ICI therapy in GI cancer and pancancer, indicating that the DRIA signature may serve as a powerful biomarker for guiding ICI therapy decisions.展开更多
Background:Nuclear receptor binding SET domain protein-3(NSD3)is a histone lysine methyltransferase and a crucial regulator of carcinogenesis in several cancers.We aimed to investigate the prognostic value and potenti...Background:Nuclear receptor binding SET domain protein-3(NSD3)is a histone lysine methyltransferase and a crucial regulator of carcinogenesis in several cancers.We aimed to investigate the prognostic value and potential function of NSD3 in 33 types of human cancer.Methods:The data were obtained from The Cancer Genome Atlas.Kaplan-Meier analysis,CIBERSORT,gene set enrichment analysis,and gene set variation analysis were performed.The expression of NSD3 was measured using quantitative real-time polymerase chain reaction and western blot.Results:The expression of NSD3 was altered in pan-cancer samples.Patients with higher levels of NDS3 generally had shorter overall survival and disease-specific survival.Levels of NSD3 were positively correlated with DNA copy number variation(CNV)in pan-cancer.NSD3 expression was also associated with tumor mutation burden and microsatellite instability.The levels of immune-cell infiltration differed significantly between high and low NSD3 expression.NSD3 negatively correlated with levels of CD8+T cells.Functional enrichment analysis showed that while NSD3 expression was positively associated with several immune cell-related and histone methylation-related pathways,it was negatively correlated with cell metabolism-related,drug transport-related,and drug metabolismrelated pathways.NSD3 levels in the cell lines tested were significantly different.In U251 and NCI-H23 cells,silencing NSD3 inhibited cell proliferation and promoted apoptosis.Conclusions:NSD3 expression was changed in pan-cancer samples that was also verified in cell lines.NSD3 was associated with CNV and immune-cell infiltration.A poor prognosis was predicted in patients with high expression of NSD3.NSD3 might hence be a potential marker for predicting tumor prognosis.展开更多
Accumulating evidence in recent years indicates that DNA methylation(5-methyl-2-deoxycytidine,5-mdC) and hydroxymethylation(5-hydroxymethyl-2-deoxycytidine, 5-hmd C) have been implicated in various biological processe...Accumulating evidence in recent years indicates that DNA methylation(5-methyl-2-deoxycytidine,5-mdC) and hydroxymethylation(5-hydroxymethyl-2-deoxycytidine, 5-hmd C) have been implicated in various biological processes, and the aberrations of these DNA cytosine modifications is tightly associated with cancer. N6-methyl-2-deoxyadenosine(m~6dA), as a newly discovered epigenetic modification in genome of mammals, has been demonstrated to play vital regulatory roles in tumorigenesis. However, the content information of m~6dA in human tumor tissues is still limited and pan-cancer analysis of these DNA epigenetic modifications is lacked. Herein, we developed a sensitive and robust stable isotopediluted hydrophilic interaction liquid chromatography-tandem mass spectrometry(HILIC-MS/MS) method for accurate quantification of m~6dA, 5-mdC and 5-hmdC in genomic DNA from 82 pairs of human tumor tissues and matched tumor-adjacent normal tissues. The types of tumors included esophagus cancer, lung cancer, breast cancer, liver cancer, pancreatic cancer, gastric cancer, stromal tumor and colorectal cancer.Compared to the normal tissues, we revealed the level of m6dA was increased in tumor tissues of esophagus cancer, lung cancer and liver cancer, whereas the level of m~6dA was diminished in tumor tissues of pancreatic cancer and gastric cancer;while the contents of 5-mdC and 5-hmdC exhibited significant decrease in tumor tissues of most types of cancer. It is worth noting that we revealed, for the first time,the content of genomic m~6dA in pancreatic cancer, stromal tumor and colorectal cancer. The significant changes of these DNA epigenetic modifications indicate they may serve as indicators of cancers. In addition, this study will benefit for better understanding of the regulatory roles of these DNA epigenetic modifications in cancers.展开更多
Background:Protein lactylation is a new way for the“metabolic waste”lactic acid to perform novel functions.Nevertheless,our understanding of the contribution of protein lactylation to both tumor progression and ther...Background:Protein lactylation is a new way for the“metabolic waste”lactic acid to perform novel functions.Nevertheless,our understanding of the contribution of protein lactylation to both tumor progression and therapeutic interventions remains imited.The construction of a scoring system for lactylation to predict the prognosis of pancancer patients and to evaluate the tumor immune microenvironment(TIME)would improve our understanding of the clinical significance of lactylation.Methods:Consensus clustering analysis of lactylation-related genes was used to cluster 177 pancreatic adenocarcinoma(PAAD)patients.Subsequently,a scoring system was developed using the least absolute shrinkage and selection operator(LASSO)regression.Internal validation and external validation were both conducted to assess and confirm the predictive accuracy of the scoring system.Finally,leucine rich repeat containing 1(LRRC1),a newly discovered lactylation-related gene,was analyzed in PAAD in vitro.Results:Utilizing the profiles of 332 lactylation-related genes,a total of 177 patients with PAAD were segregated into two distinct groups.LacCluster^(high) patients had a poorer prognosis than LacCluster^(low) patients.Through the differential analysis between the LacCluster^(high) and LacCluster^(low) groups,we identified additional genes associated with lactylation.These genes were then integrated to construct the LacCluster-enhanced system,which enabled more accurate prognosis prediction for patients with PAAD.Then,a lactylation index containing three genes(LacI-3)was constructed using LASSO regression.This was done to enhance the usability of the LacCluster-enhanced system in the clinic.Compared to those in the LacI-3^(high) subgroup,patients in the LacI-3^(low) subgroup exhibited increased expression of immune checkpoint-related genes,more immune cell infiltration,lower tumor mutation burdens,and better prognoses,indicating a“hot tumor”phenotype.Moreover,knocking down the expression of LRRC1,the hub gene in the LacI-3 scoring system,inhibited PAAD cell invasion,migration,and proliferation in vitro.Ultimately,the significance of LacI-3 across cancers was confirmed.Conclusion:Our findings strongly imply that protein lactylation may represent a new approach to diagnosing and treating malignant tumors.展开更多
Tumor tissues contain both tumor and non-tumor cells,which include infiltrated immune cells and stromal cells,collectively called the tumor microenvironment(TME).Single-cell RNA sequencing(sc RNAseq)enables the examin...Tumor tissues contain both tumor and non-tumor cells,which include infiltrated immune cells and stromal cells,collectively called the tumor microenvironment(TME).Single-cell RNA sequencing(sc RNAseq)enables the examination of heterogeneity of tumor cells and TME.In this review,we examined sc RNAseq datasets for multiple cancer types and evaluated the heterogeneity of major cell type composition in different cancer types.We further showed that endothelial cells and fibroblasts/myofibroblasts in different cancer types can be classified into common subtypes,and the subtype composition is clearly associated with cancer characteristic and therapy response.展开更多
The incre asing interest in RNA modifications has signifcantly advanced epigenomic and epitranscriptomic technologies.This study focuses on the immuno oncological impact of ALYREF in human cancer through a pan-cancer ...The incre asing interest in RNA modifications has signifcantly advanced epigenomic and epitranscriptomic technologies.This study focuses on the immuno oncological impact of ALYREF in human cancer through a pan-cancer analysis,enhancing understanding of this gene's role in cancer.We observed differential ALYREF expression between tumor and normal samples,correl ating strongly with prognosis in various cancers,particularly kidney renal papillary cell carcinoma(KIRP)and liver hepatocellular carcinoma(LIHC).ALYREF showed a negative correlation with most tumor-infitrating cells in lung squamous cell carcinoma(LUSC)and lymphoid neoplasm difuse large B-cell lymphoma(DLBC),while positive correlations were noted in IIHC,kidney chromophobe(KICH),mesothelioma(MESO),KIRP,pheochromocytoma and paraganglioma(PARD),and glioma(GBMLGG).Aditionally,ALYREF expression was closely associated with tumor heterogeneity,stemness indices,and a high mutation rate in TP53 across these cancers.In conclusion,ALYREF may serve as an oncogenic biomarker in numerous cancers,meriting further research attention.展开更多
Objective Glutamine fructose-6-phosphate transaminase 2(GFPT2)is involved in a wide range of biological functions in human cancer.However,few studies have comprehensively analyzed the correlation between GFPT2 and dif...Objective Glutamine fructose-6-phosphate transaminase 2(GFPT2)is involved in a wide range of biological functions in human cancer.However,few studies have comprehensively analyzed the correlation between GFPT2 and different cancer prognoses and tumor microenvironments(TMEs).Methods We evaluated the expression level and prognostic value of GFPT2 using updated public databases and multiple comprehensive bioinformatics analysis methods and explored the relationship between GFPT2 expression and immune infiltration,immune neoantigens,tumor mutational burden(TMB),and microsatellite instability in pan-cancer.Results GFPT2 was highly expressed in five cancers.GFPT2 expression correlates with the prognosis of several cancers from The Cancer Genome Atlas(TCGA)and is significantly associated with stromal and immune scores in pan-cancer.High GFPT2 expression in BLCA,BRCA,and CHOL was positively correlated with the infiltration of immune cells,such as B-cells,CD4+T,CD8+T cells,dendritic cells,neutrophils,and macrophages.Conclusion High GFPT2 expression may modify the outcomes of patients with BLCA,BRCA,or CHOL cancers by increasing immune cell infiltration.These findings may provide insights for further investigation into GFPT2 as a potential target in pan-cancer.展开更多
基金supported by grants from the Tianjin Health Technology Project(Grant no.2022QN106).
文摘Background:Receptor-interacting protein kinases(RIPKs)regulate cell death,inflammation,and immune responses,yet their roles in cancer are not fully understood.This study investigates the expression,genomic alterations,and functional implications of RIPK family members across various cancers.Methods:We collected multi-omics data from The Cancer Genome Atlas and other public databases,including gene expression,copy number variation(CNV),mutation,methylation,tumor mutation burden(TMB),and microsatellite instability(MSI).Differential expression and survival analyses were performed using DESeq2 and Cox proportional hazards models.CNV and mutation data were analyzed with GISTIC2 and Mutect2,and methylation data with the ChAMP package.Correlations with TMB and MSI were assessed using Pearson coefficients,and gene set enrichment analysis was conducted with the MSigDB Hallmark gene sets.Results:RIPK family members show significant differential expression in various cancers,with RIPK1 and RIPK4 frequently altered.Survival analysis reveals heterogeneous impacts on overall survival.CNV and mutation analyses identify high alteration frequencies for RIPK2 and RIPK7,affecting gene expression.RIPK1 and RIPK7 are hypermethylated in several cancers,inversely correlating with RIPK3 expression.RIPK1,RIPK2,RIPK5,RIPK6,and RIPK7 correlate positively with TMB,while RIPK3 shows negative correlations in some cancers.MSI analysis indicates associations with DNA mismatch repair.G ene set enrichment analysis highlights immune-related pathway enrichment for RIPK1,RIPK2,RIPK3,and RIPK6,and cell proliferation and DNA repair pathways for RIPK4 and RIPK5.RIPK family members showed heterogeneous alterations across cancers:for example,RIPK7 was mutated in up to~15%of u terine c orpus e ndometrial c arcinoma and l ung s quamous c ell c arcinoma cases,and RIPK1 and RIPK7 exhibited frequent promoter hypermethylation in multiple tumor types.Several genes displayed context-dependent associations with overall survival and with TMB/MSI.Conclusion:This pan-cancer analysis of the RIPK family reveals their diverse roles and potential as biomarkers and therapeutic targets.The findings emphasize the importance of RIPK genes in tumorigenesis and suggest context-dependent functions across cancer types.Further studies are needed to explore their mechanisms in cancer development and clinical applications.
基金supported by the NationalNatural Science Foundation of China(no.32360888)the Jiangxi Students’Platform for Innovation and Entrepreneurship Training Program(no.202411843023).
文摘Background:Heat shock protein B8(HSPB8)is implicated in autophagy,and its aberrant expression has been linked to both the ini-tiation and progression of tumors.However,the role and function of HSPB8 in colorectal cancer(CRC)and across multiple cancer types remain unclear.This study aimed to map the transcriptome of autophagy-related genes in CRC and to conduct a pan-cancer analysis of HSPB8 as both a prognostic and immunological biomarker.Methods:We performed bioinformatics analyses on GSE113513 and GSE74602 to identify differentially expressed genes(DEGs)in CRC.These DEGs were then compared with autophagy-related genes to identify critical overlapping genes.The Kaplan-Meier plotter was used to verify the ex-pression of autophagy-linked DEGs and evaluate its prognostic value.The protein expression of Hub gene in CRC was analyzed using the Human Protein Atlas database.The cBioPortal was used to analyze the type and frequency of Hub gene mutations.The TIMER(Tumor Immune Estimation Resource)database was used to study the correlation between HSPB8 and immune infiltration in CRC.Results:In total,825 DEGs were identified,including 8 autophagy-linked DEGs:ATIC,MYC,HSPB8,TNFSF10,BCL2,TP53INP2,ITPR1,and NKX2-3.Survival analysis showed that increased HSPB8 expression significantly correlates with poor prognosis in patients with CRC(p<0.05).HSPB8 was also found to be differentially expressed in various cancer types,correlating with both prognosis and immune infiltration.Further,changes in HSPB8 methylation and phosphorylation status were observed across several cancers,suggesting potential regulatory mechanisms.Therefore,HSPB8 may serve as a crucial prognostic and immunological biomarker in CRC and other cancers.Conclusions:This study provides new insights into the role of autophagy-related genes in cancer progression and highlights HSPB8 as a potential target for cancer diagnostics and therapy.
文摘Background:Aberrant expression of RNA-binding proteins(RBPs)has been linked to a variety of diseases,including hematological disorders,cardiovascular diseases,and multiple types of cancer.Heterogeneous nuclear ribonucleoprotein C(HNRNPC),a member belonging to the heterogeneous nuclear ribonucleoprotein(hnRNP)family,plays a pivotal role in nucleic acid metabolism.Previous studies have underscored the significance of HNRNPC in tumorigenesis;however,its specific role in malignant tumor progression remains inadequately characterized.Methods:We leveraged publicly available databases,including The Cancer Genome Atlas(TCGA),to explore the potential involvement of HNRNPC across various cancers.Additionally,we performed experimental validation studies focused on liver cancer.Results:Our analysis revealed that HNRNPC is overexpressed in a wide range of common malignancies,including liver and lung cancers,and is strongly linked to unfavorable outcomes.Furthermore,HNRNPC was observed to be closely linked to tumor immunity.Through immune checkpoint analysis and immune cell infiltration assessment,HNRNPC emerged as a potential target for modulating tumor immunotherapy.Notably,silencing of HNRNPC markedly inhibited the proliferation,metastasis,and infiltration of liver cancer cells.Conclusion:In summary,our findings highlight HNRNPC as a prognostic marker in various cancers,including liver cancer,and suggest its involvement in shaping the tumor immune microenvironment.These insights offer potential avenues for improving clinical outcomes in tumors with elevated HNRNPC expression,particularly through immunotherapeutic strategies.
基金supported by grants from the Weifang Municipal Health Commission Research Programme Project(No.WFWSJK-2023-032)the Weifang Science and Technology Development Project(No.2023YX053)the Weifang Young Medical Talent Support Program Funding。
文摘Background:NDC80 is pivotal in cell division,particularly in regulating the G2/M transition and mitotic progression.Recent studies have demonstrated that NDC80 is significantly overexpressed in multiple solid tumors.Further analysis has suggested that its high expression is significantly associated with an elevated pathological grade,increased metastatic risk,and shortened overall survival in patients with cancer.However,its precise role in pan-cancer development,progression,and prognosis remains unclear.Methods:We conducted a multi-omics analysis of NDC80 using genomic,transcriptomic,and proteomic data from 33 cancer types in The Cancer Genome Atlas,Clinical Proteomic Tumor Analysis Consortium,Genotype-Tissue Expression,and Human Protein Atlas.Results:The results demonstrated frequent NDC80 mutations across multiple malignancies and significantly elevated expression in tumor tissues compared with that in their normal counterparts,correlating with worse overall and disease-free survival.Moreover,NDC80 expression was strongly associated with oncogenic pathways,key protein regulators,cellular components,myeloid-derived suppressor cell infiltration,ESTIMATE scores,and cancer-related signaling networks.Conclusions:These findings underscore the potential of NDC80 as a prognostic biomarker and therapeutic target for cancer treatment.
基金Supported by the Science and Technology Program of Gansu Province,No.23JRRA1015the International Science and Technology Cooperation Project of Gansu Provincial Science and Technology Department,No.2023YFWA0009the Innovation and Entrepreneurship Project for Young Talents of Lanzhou Science and Technology Bureau,No.2023-4-18.
文摘BACKGROUND Ectonucleoside triphosphate diphosphohydrolase 6(ENTPD6),a member of the ENTPD family,has been implicated in certain cancers,yet a comprehensive analysis across multiple cancer types remains lacking.AIM To systematically evaluate ENTPD6’s expression,prognostic significance,and functions across multiple cancer types.METHODS In this study,we performed a pan-cancer analysis to investigate the correlation between ENTPD6 expression and various factors,including prognosis,genetic alterations,epigenetic modification,immune infiltration,immunotherapy responses,functional enrichment,and drug sensitivity.A tissue microarray of gastrointestinal tumors was used to validate differential ENTPD6 protein expression.RESULTS Pan-cancer analysis revealed that ENTPD6 expression was significantly elevated in many cancers.Immunohistochemistry staining analysis revealed that ENTPD6 expression was significantly higher in esophageal carcinoma,stomach adenocarcinoma,colon adenocarcinoma,rectal adenocarcinoma,and pancreatic adenocarcinoma compared to normal tissues.Furthermore,ENTPD6 expression was strongly associated with immune-infiltrating cells,particularly clusters of differentiation 8+T cells and natural killer cells,and correlated with immune-related genomic features including tumor mutational burden and microsatellite instability.Pathway analysis indicated that ENTPD6 expression was primarily linked to purine and pyrimidine metabolism pathways.Drug sensitivity analysis revealed that high ENTPD6 expression was sensitive to RDEA119,selumetinib,and PD-0325901.CONCLUSION This pan-cancer study elucidates the pivotal role of ENTPD6 in tumor progression and establishes its potential as a therapeutic target for immunotherapeutic approaches in specific malignancies.
基金supported by a grant from the Hefei Municipal Health Commission Applied Medical Research Project(No.Hwk2023zd007)。
文摘Background:Rho GDP dissociation inhibitor 2(ARHGDIB),a key regulator of Rho GTPase,plays a significant role in the onset and progression of cancer by participating in various biological processes.However,the diverse biological roles of ARHGDIB across pan-cancer remain systematically and comprehensively unexplored.We aimed to elucidate the diagnostic and prognostic roles of ARHGDIB and its potential tumor-related mechanisms in human cancers,using bioinformatics approaches.Methods:Data on 33 tumor types were downloaded from The Cancer Genome Atlas,and R software was used to statistically analyze ARHGDIB expression levels and prognostic significance across pan-cancer.Western blot was used to verify the protein expression of ARHGDIB in breast cancer and liver cancer cell lines.Additionally,various databases,including UALCAN,GEPIA,cBioPortal,TIMER,CancerSEA,GSCALite,and GSEA,were used to examine ARHGDIB protein expression across pan-cancer,its correlation with tumor pathological staging,ARHGDIB mutation types and frequencies,and immune cell infiltration.Furthermore,functional analyses at the single-cell level,drug sensitivity assessments,and explorations of related signaling pathways were performed.Results:ARHGDIB exhibits abnormal expression at mRNA and protein levels across various cancers.Western blot results show that ARHGDIB is highly expressed in breast cancer and liver cancer cells.ARHGDIB influences the prognosis of lower-grade glioma,bladder cancer,sarcoma,and skin cutaneous melanoma.It exhibits the highest frequency of gene alterations in uterine carcinosarcoma,primarily characterized by gene amplification.Additionally,ARHGDIB is strongly associated with immune-infiltrating cells and immune checkpoints in the tumor microenvironment.It potentially influences cancer progression through multiple signaling pathways.Conclusions:ARHGDIB is a potential prognostic marker in various cancers and a crucial regulator of the tumor microenvironment.It represents a promising therapeutic target by modulating cancer progression through multiple biological behaviors and signaling pathways.
基金Supported by the National Natural Science Foundation of China,No.NSFC82160762,No.NSFC82460783Natural Science Foundation of Guangxi,No.2022GXNSFBA035657Innovation Project of Guangxi Graduate Education,No.JGY2023068,No.YCSW2023220.
文摘BACKGROUND Although transmembrane protein 106C(TMEM106C)has been elucidated to be overexpressed in cancers,its underlying mechanisms have not yet been fully understood.AIM To investigate the expression levels and molecular mechanisms of TMEM106C across 34 different cancer types,including liver hepatocellular carcinoma(LIHC).METHODS We analyzed TMEM106C expression patterns in pan-cancers using microenvironment cell populations counter to evaluate its association with the tumor microenvironment.Gene set enrichment analysis was conducted to identify molecular pathways related to TMEM106C.Chromatin immunoprecipitation followed by sequencing(ChIP-seq)analysis was conducted to identify upstream transcriptional regulators of TMEM106C.In LIHC,we examined mRNA profiles,performed in-house quantitative polymerase chain reaction,immunohistochemistry,and constructed a co-expression gene network.Functional assays,including cell counting kit-8,cell cycle,apoptosis,migration,and invasion,were conducted.The effect of nitidine chloride(NC)on LIHC xenograft was evaluated through RNA sequencing and molecular docking.Finally,potential therapeutic agents targeting TMEM106C were predicted.RESULTS TMEM106C was significantly overexpressed in 27 different cancer types and presaged poor prognosis in four of these types,including LIHC.Across pan-cancers,TMEM106C was inversely correlated to the abundances of immune and stromal cells.Furthermore,TMEM106C was significantly linked to cell cycle and DNA replication pathways in pan-cancers.ChIP-seq analysis predicted CCCTC-binding factor as a pivotal transcriptional factor targeting the TMEM106C gene in pan-cancers.Integrated analysis showed that TMEM106C was upregulated in 4657 LIHC compared with 3652 normal liver tissue[combined standardized mean difference=1.31(1.09,1.52)].Inhouse LIHC samples verified the expression status of TMEM106C.Higher TMEM106C expression signified worse survival conditions in LIHC patients treated with sorafenib,a tyrosine kinase inhibitor(TKI).Co-expressed analysis revealed that TMEM106C were significantly enriched in the cell cycle pathway.Knockout experiments demonstrated that TMEM106C plays a crucial role in LIHC cell proliferation,migration,and invasion,with cell cycle arrest occurring at the DNA synthesis phase,and increased apoptosis.Notably,TMEM106C upregulation was attenuated by NC treatment.Finally,TMEM106C expression levels were significantly correlated with the drug sensitivity of anti-hepatocellular carcinoma agents,including JNJ-42756493,a TKI agent.CONCLUSION Overexpressed TMEM106C was predicted as an oncogene in pan-cancers,which may serve as a promising therapeutic target for various cancers,including LIHC.Targeting TMEM106C could potentially offer a novel direction in overcoming TKI resistance specifically in LIHC.Future research directions include in-depth experimental validation and exploration of TMEM106C’s role in other cancer types.
文摘BACKGROUND Although chronic-phase chronic myeloid leukemia(CP-CML)is treatable and nearly curable in about 50%of patients,accelerated-phase chronic myeloid leukemia(AP-CML)shows concerning drug resistance,while blast crisis chronic myeloid leukemia(BC-CML)is highly lethal.Advances in whole exome sequencing(WES)reveal pan-cancer mutations in BC-CML,supporting mutation-guided therapies beyond Breakpoint cluster region-Abelson.Artificial intelligence(AI)and machine learning(ML)enable genomic stratification and drug repurposing,addressing overlooked actionable mutations.AIM To stratify BC-CML into molecular subtypes using WES,ML,and AI for precision drug repurposing.METHODS Included 123 CML patients(111 CP-CML,5 AP-CML,7 BC-CML).WES identified pan-cancer mutations.Variants annotated via Ensembl Variant Effect Predictor and Catalogue of Somatic Mutations in Cancer(COSMIC).ML(principal component analysis,K-means)stratified BC-CML.COSMIC signatures and PanDrugs prioritized drugs.Analysis of variance/Kruskal-Wallis validated differences(P<0.05).RESULTS In this exploratory,hypothesis-generating study of BC-CML patients(n=7),we detected over 2500 somatic mutations.ML identified three BC-CML clusters:(1)Cluster 1[breast cancer susceptibility gene 2(BRCA2),TP53];(2)Cluster 2[isocitrate dehydrogenase(IDH)1/2,ten-eleven translocation 2];and(3)Cluster 3[Janus kinase(JAK)2,colony-stimulating factor 3 receptor],with distinct COSMIC signatures.Therapies:(1)Polyadenosinediphosphate-ribose polymerase inhibitors(olaparib);(2)IDH inhibitors(ivosidenib);and(3)JAK inhibitors(ruxolitinib).Mutational burden,signatures,and targets varied significantly across clusters,supporting precision stratification.CONCLUSION This WES-AI-ML framework provides mutation-guided therapies for BC-CML,enabling real-time stratification and Food and Drug Administration-approved drug repurposing.While this exploratory study is limited by its small sample size(n=7),it establishes a methodological framework for precision oncology stratification that warrants validation in larger,multi-center cohorts.
基金funded by the Central to guide local scientific and Technological Development(ZYYDDFFZZJ-1)Natural Science Foundation of Gansu Province,China(No.18JR3RA052)+2 种基金Lanzhou Talent Innovation and Entrepreneurship Project Task Contract(No.2016-RC-56)Gansu Da Vinci Robot High-End Diagnosis and Treatment Team Construction Project,and Gansu Provincial Youth Science and Technology Fund Program(20JR10RA415)National Key Research and Development Program(No.2018YFC1311500).
文摘B and T-lymphocyte attenuator(BTLA)plays an immunosuppressive role by inhibiting T-and B-cell functions.BTLA is associated with a variety of diseases,especially cancer immunity.However,the function of BTLA in various cancers and its clinical prognostic value have still not been comprehensively analyzed.This study aimed to identify the relationship between BTLA and cancer from the perspectives of differences in BTLA expression,its clinical value,immune infiltration,and the correlation with immune-related genes in various cancers.Data regarding mRNA expression,miRNA expression,lncRNA expression,and clinical data of patients of 33 existing cancers were collected from the TCGA database.Target miRNA of BTLA and the lncRNA that interacts with the target miRNA were obtained from the StarBase database.Based on bioinformatics analysis methods,the relationship between various types of cancers and BTLA was thoroughly investigated,and a competing endogenous RNA network of BTLA,target miRNA,and interacting lncRNA was constructed.The Kaplan-Meier(KM)prognostic analysis of BTLA and target miRNA(has-miR-137)in various types of cancers was completed using the KM plotter.BTLA expression varied in different cancers,with statistical significance in nine cancer types.KM plotter to analyze the overall survival(OS)and regression-free survival prognosis of cancer patients revealed that the BTLA expression was statistically different in the OS of 11 types of cancers out of 21 types of cancers;the OS of 8 type of cancers was also statistically different.Correlation analysis of tumor immune genes revealed a positive correlation of BTLA expression with immunosuppressive gene(CTLA4 and PDCD1)expression.Gene Set Enrichment Analysis showed that BTLA and its co-expressed genes mainly act through biological processes and pathways,including immune response regulation,cell surface receptor signaling pathway,antigen binding,antigen receptor-mediated signaling pathway,and leukocyte migration.BTLA has the potential as a prognostic marker for CLL,COAD,NSCLC,and OV and a diagnostic marker for CLL,COAD,and KIRC.BTLA has a close and complex relationship with the occurrence and development of tumors,and cancer immunotherapy for BTLA is worthy of further analysis.
基金supported by the Pujiang Talent Program from Shanghai Municipal Human Resource Bureau and Shanghai Science and Technology Committee to Shoukai Yu.The Grant No.is 19PJC085.
文摘Apolipoprotein E(APOE),a gene identified as one of the strongest genetic factors contributing to the risk determinant of developing late-onset Alzheimer’s disease(AD),may also contribute to the risk of cancer.However,no pan-cancer analysis has been conducted specifically for the APOE gene.In this study,we investigated the oncogenic role of the APOE gene across cancers by GEO(Gene Expression Omnibus)and TCGA(The Cancer Genome Atlas).Based on the available data,we found that most cancer types overexpress APOE,and clear associations exist between the expression level of APOE and prognosis in tumor patients.The expression of APOE also correlates with certain gender-associated tumors including,ovarian cancer,uterine carcinosarcoma,and breast cancer.However,there is a significant negative association between cancer-associatedfibroblast infiltration levels and the expression level of APOE in testicular germ cell tumors.Moreover,acute inflammatory response and protein-activation cascade-associated functions play an important role in the functional mechanisms of APOE.The present pan-cancer analysis of APOE shows that the protein phosphorylation,DNA methylation,and genetic alterations of APOE have a significant clinical relevance for survival prognosis and immune cell infiltration.This novel pan-cancer study outlines the current understanding of APOE oncogenic roles across thirty-three cancers and highlights the complex association between AD and cancers.
基金supported by Zhejiang Basic Public Welfare Research Project(No.LGF18H160040)。
文摘Objective:Ankyrin repeat domain-containing protein 6(ANKRD6)is an ankyrin repeat-containing protein which is structurally related to vertebrate inversin and Drosophila Diego.However,the correlations between ANKRD6 and tumor-infiltrating immune cells in cancers is not clear.Methods:ANKRD6 expression was analyzed by Oncomine,Tumor Immune Estimation Resource(TIMER)and Gene Expression Profiling Interactive Analysis(GEPIA).PrognoScan and GEPIA were used to evaluate the influence of ANKRD6 on clinical prognosis.TIMER and CIBERSORT were used to analyze correlations between ANKRD6 expression levels and tumor immune cell infiltrates.Immunohistochemical analysis of the relationship between ANKRD6 expression and overall survival,as well as the relationship between ANKRD6 expression and M2 macrophage infiltration,was performed.Results:High level of ANKRD6 expression was associated with poor prognosis of colon cancer.ANKRD6 expression level was positively correlated with infiltrating levels of CD8+T cells,CD4+T cells,macrophages,neutrophils and dendritic cells in colon cancer by using TIMER.Using CIBERSORT,we found that in plasma cells,CD8+T cells,CD4+memory resting T cells,follicular helper T cells and activated natural killer cells were significantly lower in the ANKRD6-high group than in the ANKRD6-low group.M0 and M2 macrophages were significantly higher in the ANKRD6-high group than in the ANKRD6-low group.Immunohistochemistry confirmed that M2 macrophage infiltration in the ANKRD6-high group significantly increased.Conclusions:The high ANKRD6 expression is associated with poor prognosis of colon cancer.ANKRD6 expression is positively correlated with M2 macrophage infiltration in colon cancer.
基金This work was mainly supported by the Science and Technology Innovation Fund Project of Shanghai Jinshan District Science and Technology Commission(No.2021-3-55)All sponsors or funders played no roles in the study design,data collection and analysis,decision to publish,or preparation of the manuscript.
文摘Sterol o-acyltransferase1(SOAT1)is an enzyme that regulates lipid metabolism.Nevertheless,the predictive value of SOAT1 regarding immune responses in cancer is not fully understood.Herein,we aimed to expound the predictive value and the potential biological functions of SOAT1 in pan-cancer.Raw data related to SOAT1 expression in 33 different types of cancer were acquired from The Cancer Genome Atlas(TCGA)and Genotype-Tissue Expression(GTEx)databases.SOAT1 expression was significantly increased in most cancers and showed a distinct correlation with prognosis.This enhanced expression of the SOAT1 gene was confirmed by evaluating SOAT1 protein expression using tissue microarrays.In addition,we found significant positive associations between SOAT1 expression levels and infiltrating immune cells,including T cells,neutrophils,and macrophages.Moreover,the co-expression analysis between SOAT1 and immune genes showed that many immune-related genes were increased with enhanced SOAT1 expression.A gene set enrichment analysis(GSEA)revealed that the expression of SOAT1 correlated with the tumor microenvironment,adaptive immune response,interferon signaling,and cytokine signaling.These findings indicate that SOAT1 is a potential candidate marker for predicting prognosis and a promising target for tumor immunotherapy in cancers.
基金supported by the National Natural Science Foundation of China(no.82374229 and 82172839).
文摘Background:Both eczema and tumor are associated with immune disorders.Although several investigations have observed the rela-tionship between eczema and certain cancers,evidence for causality is lacking.Methods:We conducted a two-sample Mendelian randomization(MR)study to examine and explore the genetic association between eczema and pan-cancers.Upon satisfying the three core assumptions of MR,we analyzed the causality between eczema and 15 site-specific cancers utilizing an inverse variance weighted method.We verified the results through a series of sensitivity and reverse direction analyses.The exposure and outcome datasets were substituted from the FinnGen and genome-wide association studies catalog data-bases.A meta-analysis on primary and validation analyses was performed to combine the estimates of MR study.Results:Based on the MR analysis results,eczema was associated with an increased risk of lung cancer(odds ratio[OR]=1.0427,95%confidence interval[CI]=1.0082–1.0783,P=0.0148)and brain cancer(OR=1.0285,95%CI=1.0120–1.0452,P=0.0007)and de-creased risk of colorectal cancer(OR=0.9324,95%CI=0.8774–0.9909,P=0.0242)and malignant neoplasm of the kidney(OR=0.9323,95%CI=0.8834–0.9839,P=0.0108).The sensitivity analysis indicated that the results were stable and reliable,and the reverse MR analyses demonstrated no causation between the cancers of interest and eczema.Conclusions:Our results identified eczema as a genetic risk factor for lung and brain cancer and a protective factor for colorectal cancer and malignant neoplasm of the kidney.No connection was observed between eczema and other cancers.Further evidence from epide-miological and mechanistic studies is needed to elucidate these findings in detail.
基金supported by the National Natural Science Foundation of China (Grant Nos. 81972761 and 82202837)the National Key R&D Program of China (Grant Nos. 2016YFC1303200 and 2022YFC2505100)。
文摘Objective: DNA damage response(DDR) deficiency has emerged as a prominent determinant of tumor immunogenicity. This study aimed to construct a DDR-related immune activation(DRIA) signature and evaluate the predictive accuracy of the DRIA signature for response to immune checkpoint inhibitor(ICI) therapy in gastrointestinal(GI) cancer.Methods: A DRIA signature was established based on two previously reported DNA damage immune response assays. Clinical and gene expression data from two published GI cancer cohorts were used to assess and validate the association between the DRIA score and response to ICI therapy. The predictive accuracy of the DRIA score was validated based on one ICI-treated melanoma and three pan-cancer published cohorts.Results: The DRIA signature includes three genes(CXCL10, IDO1, and IFI44L). In the discovery cancer cohort, DRIA-high patients with gastric cancer achieved a higher response rate to ICI therapy than DRIA-low patients(81.8% vs. 8.8%;P < 0.001), and the predictive accuracy of the DRIA score [area under the receiver operating characteristic curve(AUC) = 0.845] was superior to the predictive accuracy of PD-L1 expression, tumor mutational burden, microsatellite instability, and Epstein–Barr virus status. The validation cohort demonstrated that the DRIA score identified responders with microsatellite-stable colorectal and pancreatic adenocarcinoma who received dual PD-1 and CTLA-4 blockade with radiation therapy. Furthermore, the predictive performance of the DRIA score was shown to be robust through an extended validation in melanoma, urothelial cancer, and pan-cancer.Conclusions: The DRIA signature has superior and robust predictive accuracy for the efficacy of ICI therapy in GI cancer and pancancer, indicating that the DRIA signature may serve as a powerful biomarker for guiding ICI therapy decisions.
基金supported in part by the National Natural Science Foundation of China(Grant No.81703005)the Natural Science Foundation of Hunan Province(Grant Nos.2017JJ3195,2018JJ3317)the Key Research and Development Projects of Hunan Province(Grant No.2018SK2120).
文摘Background:Nuclear receptor binding SET domain protein-3(NSD3)is a histone lysine methyltransferase and a crucial regulator of carcinogenesis in several cancers.We aimed to investigate the prognostic value and potential function of NSD3 in 33 types of human cancer.Methods:The data were obtained from The Cancer Genome Atlas.Kaplan-Meier analysis,CIBERSORT,gene set enrichment analysis,and gene set variation analysis were performed.The expression of NSD3 was measured using quantitative real-time polymerase chain reaction and western blot.Results:The expression of NSD3 was altered in pan-cancer samples.Patients with higher levels of NDS3 generally had shorter overall survival and disease-specific survival.Levels of NSD3 were positively correlated with DNA copy number variation(CNV)in pan-cancer.NSD3 expression was also associated with tumor mutation burden and microsatellite instability.The levels of immune-cell infiltration differed significantly between high and low NSD3 expression.NSD3 negatively correlated with levels of CD8+T cells.Functional enrichment analysis showed that while NSD3 expression was positively associated with several immune cell-related and histone methylation-related pathways,it was negatively correlated with cell metabolism-related,drug transport-related,and drug metabolismrelated pathways.NSD3 levels in the cell lines tested were significantly different.In U251 and NCI-H23 cells,silencing NSD3 inhibited cell proliferation and promoted apoptosis.Conclusions:NSD3 expression was changed in pan-cancer samples that was also verified in cell lines.NSD3 was associated with CNV and immune-cell infiltration.A poor prognosis was predicted in patients with high expression of NSD3.NSD3 might hence be a potential marker for predicting tumor prognosis.
基金financially supported by National Natural Science Foundation of China (No. 22176167)the Key R&D Program of Zhejiang Province (No. 2021C03125)Natural Science Foundation of Zhejiang Province (No. LY19B050007)。
文摘Accumulating evidence in recent years indicates that DNA methylation(5-methyl-2-deoxycytidine,5-mdC) and hydroxymethylation(5-hydroxymethyl-2-deoxycytidine, 5-hmd C) have been implicated in various biological processes, and the aberrations of these DNA cytosine modifications is tightly associated with cancer. N6-methyl-2-deoxyadenosine(m~6dA), as a newly discovered epigenetic modification in genome of mammals, has been demonstrated to play vital regulatory roles in tumorigenesis. However, the content information of m~6dA in human tumor tissues is still limited and pan-cancer analysis of these DNA epigenetic modifications is lacked. Herein, we developed a sensitive and robust stable isotopediluted hydrophilic interaction liquid chromatography-tandem mass spectrometry(HILIC-MS/MS) method for accurate quantification of m~6dA, 5-mdC and 5-hmdC in genomic DNA from 82 pairs of human tumor tissues and matched tumor-adjacent normal tissues. The types of tumors included esophagus cancer, lung cancer, breast cancer, liver cancer, pancreatic cancer, gastric cancer, stromal tumor and colorectal cancer.Compared to the normal tissues, we revealed the level of m6dA was increased in tumor tissues of esophagus cancer, lung cancer and liver cancer, whereas the level of m~6dA was diminished in tumor tissues of pancreatic cancer and gastric cancer;while the contents of 5-mdC and 5-hmdC exhibited significant decrease in tumor tissues of most types of cancer. It is worth noting that we revealed, for the first time,the content of genomic m~6dA in pancreatic cancer, stromal tumor and colorectal cancer. The significant changes of these DNA epigenetic modifications indicate they may serve as indicators of cancers. In addition, this study will benefit for better understanding of the regulatory roles of these DNA epigenetic modifications in cancers.
基金supported by the National Key Research and Development Program of China(Grant Number 2022YFA1205003)Major Research Projects of the National Natural Science Foundation of China(Grant Number 92059204)+1 种基金General Research Projects of the National Natural Science Foundation of China(Grant Number 82273419)Major Projects of Technological Innovation and Application Development Foundation in Chongqing(Grant Number CSTB2022TIAD-STX0012).
文摘Background:Protein lactylation is a new way for the“metabolic waste”lactic acid to perform novel functions.Nevertheless,our understanding of the contribution of protein lactylation to both tumor progression and therapeutic interventions remains imited.The construction of a scoring system for lactylation to predict the prognosis of pancancer patients and to evaluate the tumor immune microenvironment(TIME)would improve our understanding of the clinical significance of lactylation.Methods:Consensus clustering analysis of lactylation-related genes was used to cluster 177 pancreatic adenocarcinoma(PAAD)patients.Subsequently,a scoring system was developed using the least absolute shrinkage and selection operator(LASSO)regression.Internal validation and external validation were both conducted to assess and confirm the predictive accuracy of the scoring system.Finally,leucine rich repeat containing 1(LRRC1),a newly discovered lactylation-related gene,was analyzed in PAAD in vitro.Results:Utilizing the profiles of 332 lactylation-related genes,a total of 177 patients with PAAD were segregated into two distinct groups.LacCluster^(high) patients had a poorer prognosis than LacCluster^(low) patients.Through the differential analysis between the LacCluster^(high) and LacCluster^(low) groups,we identified additional genes associated with lactylation.These genes were then integrated to construct the LacCluster-enhanced system,which enabled more accurate prognosis prediction for patients with PAAD.Then,a lactylation index containing three genes(LacI-3)was constructed using LASSO regression.This was done to enhance the usability of the LacCluster-enhanced system in the clinic.Compared to those in the LacI-3^(high) subgroup,patients in the LacI-3^(low) subgroup exhibited increased expression of immune checkpoint-related genes,more immune cell infiltration,lower tumor mutation burdens,and better prognoses,indicating a“hot tumor”phenotype.Moreover,knocking down the expression of LRRC1,the hub gene in the LacI-3 scoring system,inhibited PAAD cell invasion,migration,and proliferation in vitro.Ultimately,the significance of LacI-3 across cancers was confirmed.Conclusion:Our findings strongly imply that protein lactylation may represent a new approach to diagnosing and treating malignant tumors.
基金partially supported by NIH grants(Grant Nos.R01CA249175 and U19AI118610)。
文摘Tumor tissues contain both tumor and non-tumor cells,which include infiltrated immune cells and stromal cells,collectively called the tumor microenvironment(TME).Single-cell RNA sequencing(sc RNAseq)enables the examination of heterogeneity of tumor cells and TME.In this review,we examined sc RNAseq datasets for multiple cancer types and evaluated the heterogeneity of major cell type composition in different cancer types.We further showed that endothelial cells and fibroblasts/myofibroblasts in different cancer types can be classified into common subtypes,and the subtype composition is clearly associated with cancer characteristic and therapy response.
基金the Chinese Scholarship Council(Grant No.202206240086)the National Natural Science Foundation of China(Grant No.82170432)programs from Science and Technology Department of Sichuan Province(Grant No.2020YFSY0024).
文摘The incre asing interest in RNA modifications has signifcantly advanced epigenomic and epitranscriptomic technologies.This study focuses on the immuno oncological impact of ALYREF in human cancer through a pan-cancer analysis,enhancing understanding of this gene's role in cancer.We observed differential ALYREF expression between tumor and normal samples,correl ating strongly with prognosis in various cancers,particularly kidney renal papillary cell carcinoma(KIRP)and liver hepatocellular carcinoma(LIHC).ALYREF showed a negative correlation with most tumor-infitrating cells in lung squamous cell carcinoma(LUSC)and lymphoid neoplasm difuse large B-cell lymphoma(DLBC),while positive correlations were noted in IIHC,kidney chromophobe(KICH),mesothelioma(MESO),KIRP,pheochromocytoma and paraganglioma(PARD),and glioma(GBMLGG).Aditionally,ALYREF expression was closely associated with tumor heterogeneity,stemness indices,and a high mutation rate in TP53 across these cancers.In conclusion,ALYREF may serve as an oncogenic biomarker in numerous cancers,meriting further research attention.
基金Supported by a grant from the National Natural Science Foundation of China(No.81700256).
文摘Objective Glutamine fructose-6-phosphate transaminase 2(GFPT2)is involved in a wide range of biological functions in human cancer.However,few studies have comprehensively analyzed the correlation between GFPT2 and different cancer prognoses and tumor microenvironments(TMEs).Methods We evaluated the expression level and prognostic value of GFPT2 using updated public databases and multiple comprehensive bioinformatics analysis methods and explored the relationship between GFPT2 expression and immune infiltration,immune neoantigens,tumor mutational burden(TMB),and microsatellite instability in pan-cancer.Results GFPT2 was highly expressed in five cancers.GFPT2 expression correlates with the prognosis of several cancers from The Cancer Genome Atlas(TCGA)and is significantly associated with stromal and immune scores in pan-cancer.High GFPT2 expression in BLCA,BRCA,and CHOL was positively correlated with the infiltration of immune cells,such as B-cells,CD4+T,CD8+T cells,dendritic cells,neutrophils,and macrophages.Conclusion High GFPT2 expression may modify the outcomes of patients with BLCA,BRCA,or CHOL cancers by increasing immune cell infiltration.These findings may provide insights for further investigation into GFPT2 as a potential target in pan-cancer.
